PROJECT SUMMARY/ABSTRACT Affecting more than 795 million children under the age of 5, childhood undernutrition is one of the greatest impediments to the flourishing of humankind. Current dietary interventions fail to ameliorate many of the long- term sequelae of undernutrition, including linear growth-faltering (?stunting?) and abnormal central nervous system (CNS) development. This failure suggests that our understanding of the biological state of undernutrition is incomplete, and that traditional food therapies fail to target key drivers of undernutrition-dependent pathologies that manifest later in life. Work from our lab has provided the first evidence that impaired development of the gut microbiota plays a causal role in stunting. Thus, a multi-dimensional view of childhood undernutrition that considers several axes of biological state may be required to move the needle on stunting and abnormal CNS development seen in undernourished children. Recently, a highly prevalent but poorly understood condition known as Environmental enteric dysfunction (EED) has been found to cause 45% of childhood stunting globally. Aside from growth-faltering, children with EED are typically asymptomatic; thus, EED is diagnosed by biopsy and histopathologic evidence of villous blunting, crypt hyperplasia, and chronic inflammatory infiltration within the sub-lamina propria of the small intestine. Due to the challenge of obtaining upper-intestinal biopsies from children in a global health setting, most studies have relied on plasma or fecal markers (rather than histologic evidence) indicating an underlying enteropathy, severely muddling our understanding of EED pathogenesis. In addition, no validated model of EED exists, further hampering our ability to develop biomarkers and treatments for EED. The goal of this proposal is to take on a multi-dimensional view of children with biopsy confirmed EED in order to understand the molecular and microbial features that underly EED pathogenesis and that may serve as novel biomarkers and therapeutic targets. Employing proteomic and culture-independent methods to survey the biological state of children with EED, the first aim in this proposal will identify differences between healthy children and children with EED, determine the proteomic co-abundance network between the plasma and duodenal compartments of children with EED, and identify putative EED-causal upper-intestinal microbes that co-vary with duodenal proteins indicative of inflammation and injury. Leveraging the ability to manipulate microbial community composition and nutrient landscape in gnotobiotic mice, the second aim of this proposal will test the causality of the upper-intestinal microbiota in EED pathogenesis through a longitudinal study introducing microbes cultured from the upper-intestinal tract of children with EED and by sequentially removing members of this community and assessing the effects on host enteropathy. Successful completion of this proposal will unlock hidden insights into EED pathogenesis, inspiring new therapeutic approaches to combat childhood stunting and abnormal CNS development associated with childhood undernutrition.